CN102964377B - Method for preparing natural L-alpha-glycerol phosphatidylcholine - Google Patents
Method for preparing natural L-alpha-glycerol phosphatidylcholine Download PDFInfo
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- CN102964377B CN102964377B CN201210513309.1A CN201210513309A CN102964377B CN 102964377 B CN102964377 B CN 102964377B CN 201210513309 A CN201210513309 A CN 201210513309A CN 102964377 B CN102964377 B CN 102964377B
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Abstract
The invention discloses a method for preparing natural L-alpha-glyceryl phosphatide dipalmitoyl phosphatidyl choline. The method comprises the following steps of: dissolving natural lecithin having the known content of phosphatidylcholine into methyl tertiary butyl ether; filtering out undissolved substances and regulating the temperature to 5-55 DEG C; adding anhydrous low carbon alcohol and hydroxide choline into mixing liquid in a molar rate of anhydrous low carbon alcohol to phosphatidylcholine of (3:1)-(600:1)_to stir and react for 0.25-4 hours; pouring out supernate; dissolving oily precipitates with absolute ethyl alcohol and precipitating the oily precipitates by methyl tertiary butyl ether; removing the supernate after the precipitation is totally finished; repeatedly dissolving the precipitates by the absolute ethyl alcohol and precipitating the precipitates by the methyl tertiary butyl ether for 2-3 times; vacuumizing and drying obtained oily products. By the method, transesterification between the phosphatidylcholine and the anhydrous low carbon alcohol is carried out by using hydroxide choline as a catalyst and the methyl tertiary butyl ether as a solvent so as to obtain glycerol phosphatidylcholine (GPC) or natural lecithin deacylation substances using the GPC as a main part; and moreover, the method is simple in process, mild and safe in reaction conditions, and can guarantee the safety of the obtained products used as functional food addictives or medical health-care products.
Description
Technical field
The present invention relates to medicine, functional foodstuff industry and catalysis technical field, be specifically related to a kind of preparation method of natural L-α-glycerolphosphocholine.
Background technology
L-α-glycerolphosphocholine (L-α-glycerophosphocholine, hereinafter referred to as GPC) is the aqueous phospholipid of naturally occurring a kind of uniqueness in human body.Research shows, GPC not only can improve memory capability and the cognitive ability of different steps crowd, especially to the elderly, can prevention and therapy senile dementia effectively, and have certain restraining effect to the cerebral apoplexy phenomenon of the elderly; Meanwhile, it can also promote the release of human growth hormone, and teen-age height can be made to a certain extent to make moderate progress, and also effectively can regulate the hormonal balance of middle-aged people, play the effect of beauty treatment, delaying senility.Therefore, GPC can be widely used in medicine, healthcare products and functional foodstuff industry.
In recent years, occurred that some contain the functional health product of GPC and other natural phospholipid deacylated tRNA substrate, but producer adopts the method for chemosynthesis to produce GPC mostly both at home and abroad.EP0486100 after react by D-acetone glycerol and 2-oxygen-2-chloro-1,3-diepoxy phosphorus pentane again with Trimethylamine 99 open loop condensation, the raw material instability that this process is used, needs pressurized operation in simultaneous reactions process, condition harshness.D-acetone glycerol and Tosyl chloride are then first reacted 18h by EP0502357 under 0 ° of C, obtain acetone glycerol p-toluenesulfonic esters, again with the condensation reaction of phosphorylcholine tetramethyl ammonium, product GPC can be obtained after hydrolysis, although this method avoids the problem of pressurized operation, but still there is raw material instability, complex process and the higher problem of cost.Scheme disclosed in CN101544667A is after first Racemic glycidol being made Racemic glycidol p-toluenesulfonic esters, GPC is prepared again with the condensation of phosphorylcholine tetraethyl-ammonium salt, avoid the defect of raw material Racemic glycidol purifying difficulty, but reaction process more complicated, total recovery is lower.Scheme disclosed in WO2007145476 utilizes 2，3-epoxy-1-propanol and phosphorylcholine under Isopropylamine existent condition, carries out nucleophilic addition to prepare GPC, achieve certain producing effects, but require higher to material purity in process, and reaction yield is low.Usually, by the complex process of chemical method synthesis GPC, yield is low and employ poisonous chemical raw material more, and its product is used for food and medical aspect exists very large potential safety hazard.
Slough aliphatic side chains and to obtain GPC be it prepares approach as the more favourable of Medicines and Health Product and functional food additives from the natural matter such as soybean lecithin or Ovum Gallus domesticus Flavus lecithin through hydrolysis, compared with chemical method, side reaction is less, and product is more natural.Scheme disclosed in US2864848 adopts water-soluble mercury salt to make catalyzer, and phosphatide emulsion is prepared GPC in boiling Water Under solution, though raw material is natural, product yield is low, and is separated poisonous mercury salt complex process.Scheme disclosed in EP0217765 and WO90/13552 all adopts sodium methylate as catalyzer, GPC is prepared by alcoholysis soybean lecithin, this process is higher to ingredient requirement, just saponification reaction can be there is in the existence of a small amount of water, employ a large amount of organic solvent and water in product separation process simultaneously, both add cost, cause environmental pollution again.It is the technique of catalyst for ester exchange reaction that document [Chem.Phys.lipid.4.104 (1970)] reports with tetrabutylammonium, although comparatively mercury salt is gentle, and the residual edible safety still affecting product of 4-butyl ammonium.Scheme disclosed in CN102516292A is using low-boiling amine as catalyzer, preparation GPC is reacted by natural phospholipid, reaction conditions is gentle, the time is short, product purity is high, and catalyzer reclaims use by distillation mode together with methyl alcohol, simplify preparation technology, but low-boiling amine does not still possess the characteristic of totally nontoxic, there is certain threat in the security of a large amount of uses to production process and product of methyl alcohol; In this technique there is production safety hidden danger as solvent in ether simultaneously.
Summary of the invention
For existingly with natural phosphatidyl choline being that raw material prepares that the catalyzer existed in GPC technique is poisonous, solvent ether uses dangerous, reactant methanol to there is the problems such as safety risks to technique and product.The present invention, on the basis of lot of experiments, proposes a kind of preparation method of natural L-α-glycerolphosphocholine.This preparation method take bursine as catalyzer, and methyl tertiary butyl ether, as solvent, carries out transesterification reaction by phosphatidylcholine and nontoxic low-carbon alcohol, obtains GPC or the natural phospholipid deacylated tRNA substrate based on GPC.
In order to achieve the above object, the present invention adopts following technical scheme:
A preparation method for natural L-α-glycerolphosphocholine, concrete preparation process is as follows:
The natural phosphatidyl choline of known phosphatidylcholine content is dissolved in methyl tertiary butyl ether, after elimination insolubles, adjusts the temperature to 5 ~ 55 ° of C; Under this temperature condition, be 3:1 ~ 600:1 according to anhydrous low-carbon alcohol and phosphatidylcholine mol ratio, add anhydrous low-carbon alcohol and catalyzer bursine, make the consumption of bursine in reaction system be often liter of 1 ~ 30mmol, stirring reaction 0.25 ~ 4 hour; Supernatant liquor is outwelled after reaction terminates; by oily throw out anhydrous alcohol solution; and precipitate with methyl tertiary butyl ether; the completely rear abandoning supernatant of precipitation; again repeatedly with anhydrous alcohol solution and with methyl tertiary butyl ether precipitation 2 ~ 3 times; the oil product obtained is carried out vacuum-drying under Vanadium Pentoxide in FLAKES existent condition, namely obtains the mixture of the natural phospholipid deacylated tRNA substrate based on glycerolphosphocholine.
Further, described anhydrous low-carbon alcohol adopts the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol.
Further, described natural phosphatidyl choline is from the extract of soybean, yolk or pluck, and wherein the content of phosphatidylcholine is 20% ~ 98%.
The mixture of the natural phospholipid deacylated tRNA substrate that the present invention obtains comprises glycerolphosphocholine (GPC), L-ALPHA-GPE (GPE) and glyceryl phosphatide acyl Serine (GPS); because three's character is similar; and there is similar physiological function and health-care effect; when being therefore used as the additive of medicine, healthcare products and functional foodstuff in industry, three can be combined together use.Its content is relevant with raw material simultaneously, when the phosphatidylcholine content in natural phosphatidyl choline is more than 80%, obtains the GPC that purity is higher.Reaction principle of the present invention is as follows:
Wherein, R1 and R2 represents the aliphatic hydrocarbon of C13-C25; R3 represents
with
in one, the three kinds of materials obtained are respectively GPC, GPE and GPS.
Beneficial effect of the present invention is as follows:
1, bursine can the shift reaction of effective catalyze fatty acyl group as catalyzer, and the reaction times is short, mild condition; And the stability of phosphinylidyne ester bond in feed composition can be kept, thus maintain structure specific to natural phospholipid.Meanwhile, choline is common food additive, even if there be a small amount of remaining also can not affect its safe handling in the product.
2, employ in reaction process that toxicity is little, boiling point is high and the methyl tertiary butyl ether of use safety is solvent, make preparation process and product more safe and reliable.
3, preferably green dehydrated alcohol replace classical inverse should in methyl alcohol as reactant, ensured the security of products therefrom for healthcare products and medicine further.
Embodiment
The preparation method of natural L-α-glycerolphosphocholine of the present invention, concrete preparation process is as follows:
The natural phosphatidyl choline of known phosphatidylcholine content is dissolved in methyl tertiary butyl ether, after elimination insolubles, adjusts the temperature to 5 ~ 55 ° of C; Under this temperature condition, be 3:1 ~ 600:1 according to anhydrous low-carbon alcohol and phosphatidylcholine mol ratio, add anhydrous low-carbon alcohol and catalyzer bursine, make the consumption of bursine in reaction system be often liter of 1 ~ 30mmol, stirring reaction 0.25 ~ 4 hour; Supernatant liquor is outwelled after reaction terminates; by oily throw out anhydrous alcohol solution; and precipitate with methyl tertiary butyl ether; the completely rear abandoning supernatant of precipitation; again repeatedly with anhydrous alcohol solution and with methyl tertiary butyl ether precipitation 2 ~ 3 times; the oil product obtained is carried out vacuum-drying under Vanadium Pentoxide in FLAKES existent condition, namely obtains the mixture of the natural phospholipid deacylated tRNA substrate based on glycerolphosphocholine.
Even if described catalyzer bursine has a small amount of remaining also can not affect its safe handling in the product, its free choline is additive conventional in food.
Described methyl tertiary butyl ether toxicity is little, boiling point is high and use safety, and the methyl tertiary butyl ether in the present invention also can dissolving lecithins and safety low-poison solvent with other.
Described dehydrated alcohol also can substitute by the one in methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol, but preferred dehydrated alcohol.This is because dehydrated alcohol has environmental protection and the advantage such as renewable, ensure that the security of products therefrom for healthcare products and medicine.
Described natural phosphatidyl choline is from the extract of soybean, yolk or pluck, and wherein the content of phosphatidylcholine is 20% ~ 98%.
Catalyzer in the present invention, is not only applicable to the preparation of L-α-glycerolphosphocholine, is also applicable to the extensive transesterification reactions such as the preparation of biofuel.The natural phospholipid deacylated tRNA substrate that simultaneously the present invention obtains both can directly apply to medicine, healthcare products and functional food field, also can be used as the precursor of semi-synthetic phosphatide, for the preparation of synthetic phospholipid needed for pharmaceutical preparation.
Embodiment 1
By 5g phosphatidylcholine content be 40% soybean lecithin be dissolved in 38mL methyl tertiary butyl ether, elimination insolubles, add round-bottomed flask and be placed in thermostat water bath and be heated to 40 ° of C, under this temperature condition, add the ethanolic soln that 1.2mL dehydrated alcohol and 0.8mL concentration are the bursine of 0.3mol/L again, stirring reaction 2 hours.
Supernatant liquor is outwelled after reaction terminates, oily throw out 5mL anhydrous methanol is dissolved, and add 20mL methyl tertiary butyl ether and precipitate, the completely rear abandoning supernatant of precipitation, repeat the operation precipitated with dissolve with methanol and with methyl tertiary butyl ether for 3 times again, finally the oil product obtained is carried out vacuum-drying under Vanadium Pentoxide in FLAKES existent condition, obtaining 1.021g outward appearance is flaxen natural phospholipid deacylated tRNA substrate (the i.e. GPC based on GPC, the mixture of GPE and GPS), after testing, wherein the content of GPC accounts for 50.3% of product total mass, yield is 76.0%.
Embodiment 2
The difference of the present embodiment and embodiment 1 is, by 5g phosphatidylcholine content be 60% soybean lecithin be dissolved in 30mL methyl tertiary butyl ether, elimination insolubles, add round-bottomed flask and be placed in thermostat water bath and be heated to 50 ° of C, under this temperature condition, add the ethanolic soln that 8mL dehydrated alcohol and 2mL concentration are the bursine of 0.3mol/L again, stirring reaction 1 hour.It is the flaxen natural phospholipid deacylated tRNA substrate (i.e. the mixture of GPC, GPE and GPS) based on GPC that the present embodiment obtains 1.086g outward appearance, and after testing, wherein the content of GPC accounts for 73.2% of product total mass, and yield is 78.4%.
Embodiment 3
The difference of the present embodiment and embodiment 2 is only that in soybean lecithin, phosphatidylcholine content is 95%, and temperature of reaction is 40 ° of C, and the reaction times is 3h.After reaction, oily throw out 5mL anhydrous methanol in bottom is dissolved, add 20mL methyl tertiary butyl ether again to precipitate, the completely rear abandoning supernatant of precipitation, repeatedly carry out the operation precipitated with dissolve with methanol and with methyl tertiary butyl ether for 3 times, then vacuum drying treatment is carried out by under product Vanadium Pentoxide in FLAKES existent condition, and under diatomite existent condition, the dehydrated alcohol utilizing volume ratio to be 6:4 and the mixed solution of ether carry out crystallization under 4 ° of C, obtain GPC crystal 1.026g.Fusing point 133 ° of C,
(aqueous solution of 10%), results of elemental analyses is: C, 37.1%; H, 7.80%; N, 5.43%.Take deuterated methanol as solvent,
1the position of main peaks: 4.36 (m, 2H), 3.91 (m, 2H), 3.82 (m, 1H), 3.61 (m, 2H), 3.58 (m, 2H), 3.27 (s, 9H) in H NMR spectrogram.
Embodiment 4
The difference of the present embodiment and embodiment 3 is, is that the soybean lecithin of 90% is dissolved in 30mL methyl tertiary butyl ether, adds 10mL dehydrated alcohol and 0.145 bursine, temperature of reaction 30 ° of C, stirring reaction 0.3 hour by 2g phosphatidylcholine content.The present embodiment obtains 0.409g outward appearance and is close to as colourless GPC, and purity is higher, and yield is 67.2%.
Embodiment 5
The difference of the present embodiment and embodiment 2 is, by 1g phosphatidylcholine content be 90% soybean lecithin be dissolved in 25mL methyl tertiary butyl ether, add round-bottomed flask and be placed in thermostat water bath and be heated to 25 ° of C, under this temperature condition, add the ethanolic soln that 11.5mL dehydrated alcohol and 3.5mL concentration are the bursine of 0.3mol/L again, stirring reaction 4 hours.The present embodiment obtains 0.132g outward appearance and is close to as colourless GPC, and yield is 43.4%.
Embodiment 6
The difference of the present embodiment and embodiment 5 is, by 0.4g phosphatidylcholine content be 95% soybean lecithin be dissolved in 25mL methyl tertiary butyl ether, regulate its temperature to 5 ° C, under this temperature condition, add the ethanolic soln that 13mL dehydrated alcohol and 2mL concentration are the bursine of 0.3mol/L again, stirring reaction 4 hours.The present embodiment obtains 0.0696g outward appearance and is close to as colourless GPC, and purity is higher, and yield is 54.2%.
Embodiment 7
The difference of the present embodiment and embodiment 3 is, adopts propyl carbinol to replace ethanol to react in reaction.The present embodiment obtains 0.832g outward appearance and is close to as colourless GPC, and yield is 54.6%.
Claims (2)
1. a preparation method for natural L-α-glycerolphosphocholine, it is characterized in that, concrete preparation process is as follows:
The natural phosphatidyl choline of known phosphatidylcholine content is dissolved in methyl tertiary butyl ether, after elimination insolubles, adjusts the temperature to 5 ~ 55 DEG C; Under this temperature condition, be 10:1 ~ 600:1 according to anhydrous low-carbon alcohol and phosphatidylcholine mol ratio, add anhydrous low-carbon alcohol and catalyzer bursine, make the consumption of bursine in reaction system be often liter of 1 ~ 30mmol, stirring reaction 0.25 ~ 4 hour; Supernatant liquor is outwelled after reaction terminates, by oily throw out anhydrous alcohol solution, and precipitate with methyl tertiary butyl ether, the completely rear abandoning supernatant of precipitation, again repeatedly with anhydrous alcohol solution and with methyl tertiary butyl ether precipitation 2 ~ 3 times, the oil product obtained is carried out vacuum-drying under Vanadium Pentoxide in FLAKES exists, namely obtains the mixture of the natural phospholipid deacylated tRNA substrate based on glycerolphosphocholine; Described anhydrous low-carbon alcohol adopts the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol.
2. the preparation method of natural L-α-glycerolphosphocholine as claimed in claim 1, is characterized in that, described natural phosphatidyl choline is from the extract of soybean, yolk or pluck, and wherein the content of phosphatidylcholine is 20% ~ 98%.
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| EP3060202A1 (en) * | 2013-10-21 | 2016-08-31 | Enzymotec Ltd. | Compositions comprising choline and derivatives thereof, uses thereof and processes for their preparation |
| US20170101425A1 (en) * | 2014-06-10 | 2017-04-13 | Chemi S.P.A. | Process for the purification of l-alpha-glycerophosphorylcholine |
| CN108516989A (en) * | 2018-05-18 | 2018-09-11 | 榆林学院 | A kind of preparation method of phosphatide deacylation substratess |
| CN109265478B (en) * | 2018-10-30 | 2021-07-06 | 榆林学院 | Method for preparing glycerophosphatidylcholine based on egg shells |
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